不同1p杂合性缺失特征少枝胶质瘤的差异蛋白质组学研究
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摘要
胶质瘤是颅内最常见的肿瘤,发病率高,但治愈率低。尽管外科新技术的发展以及化疗、放疗的广泛应用使得胶质瘤的预后有所改善,但是大多数胶质瘤的预后仍然较差。少枝胶质瘤(Oligodendroglioma, OG)是胶质瘤的主要类型之一,占胶质瘤的4-15%,占所有原发脑肿瘤的2-5%,由于近年来发现其对化疗较为敏感、预后较好而成为胶质瘤研究的热点。近期研究发现这些对化疗敏感的少枝胶质瘤大都有lp/19q的杂合性缺失(Loss of heterozygosity, LOH)。进一步的研究显示具有不同1p/19q LOH(或1p LOH)特征的这两类肿瘤在很多方面还有差异,如好发部位、肿瘤对放疗的敏感性及最终的预后等等。这些都说明在光镜下无法区分的这两种肿瘤可能是两类分子生物学特征不同的肿瘤,对它们的分型可能有助于临床的治疗和预后的判断。但是目前除了1p/19q染色体的差异以外,人们对这两类肿瘤的其它差异如基因表达、蛋白差异乃至最终的分子生物学机制仍然知之不多,所以有必要对此进一步的研究。
蛋白质组学分析是一个能同时研究大量蛋白质及其表达变化的方法,正逐渐应用于从基础科学到临床实践科学的广泛领域中,受到前所未有的重视。在人类基因组计划的推动下,人们从基因水平对肿瘤进行了广泛的研究,并且发现了许多与肿瘤相关的基因,包括一些与肿瘤治病有关的致癌基因和抑癌基因,但基因的功能活动最终要靠蛋白质来体现。众所周知,从DNA-mRNA-蛋白质的过程中存在着转录后剪切和翻译后的修饰加工,以及蛋白质合成后的转移定位等多种变化,所以DNA和mRNA的水平和状况并不完全代表蛋白质的水平和状况。而以往的蛋白质研究方法如Western blot等一次只能对一个或几个蛋白质的表达进行研究。但我们现在知道肿瘤的分子生物学机制都是涉及成百上千个蛋白活动的过程,因此,有必要从蛋白质整体水平来研究、寻找出与肿瘤相关的特征蛋白质,阐明其机制。同位素标记相对和绝对定量(iTRAQ)技术是近年来新开发的一种蛋白质组学定量研究技术,具有较好的定量效果、较高的重复性,并可对多达8种不同样本同时进行定量分析。因此,iTRAQ标记-串联质谱分析技术是寻找疾病和肿瘤发生过程中的标志性蛋白或者称为Biomarker的理想方法。我们此次使用iTRAQ技术结合多维液相色谱串联质谱(2D-LC MS/MS)对不同1pLOH特征的少枝胶质瘤组织进行比较蛋白质组分析,寻找特异蛋白作为诊断标志并进一步探求不同少枝胶质瘤的发病机制。
第一部分荧光原位杂交技术检测少枝胶质瘤1p染色体的杂合性缺失
目的：研究少枝胶质瘤中1p染色体的杂合性缺失。
方法：使用荧光原位杂交技术对16例少枝胶质瘤标本及5例正常对照脑组织行1p染色体检测。
结果：在16例少枝胶质瘤中有10例有1p染色体的杂合性缺失,占62.5%,其中6例Ⅱ级肿瘤中有5例缺失,10例Ⅲ级肿瘤中有5例缺失。
结论：1p染色体杂合性缺失是少枝胶质瘤的重要分子生物学特征,通过荧光原位杂交技术,我们可以对这两类少枝胶质瘤有效地加以区分,并用于进一步的临床诊断和治疗。
第二部分基于iTRAQ技术的少枝胶质瘤差异蛋白质组分析
目的：对不同1p LOH特征的少枝胶质瘤进行差异蛋白质组分析,寻找特异蛋白用于诊断和治疗。
方法：使用同位素标记相对和绝对定量(iTRAQ)技术结合多维液相色谱串联质谱(2D-LC MS/MS)的定量蛋白质组学方法对8例不同1p LOH特征的两组少枝胶质瘤进行分析,并用DAVID、KEGG软件对数据进一步处理行生物信息学分析,通过统计分析找出差异蛋白质。
结果：通过蛋白质组分析在8例少枝胶质瘤中共鉴定得到449个蛋白质,统计分析发现HMGB1、MAP2、TMSB4X、LRPAP1、MARCKSL1、RPLP2、CISD1、ATP6V1E1、PSAP、PPIF、ARPC5L这11个蛋白在1p LOH的OG中表达较1p正常组肿瘤高,UBA1、PRKAR1A两个蛋白在1p正常的OG中表达较1p LOH组肿瘤高。
结论：在两组不同1p LOH特征的少枝胶质瘤中找到多个有差异表达的蛋白质,较其它蛋白质组学方法找到的蛋白谱范围更广；生物信息学分析显示Actin cytoskeleton通路的不同可能与这两类肿瘤的不同机制有关,HMGB1、UBA1可能与OG的化疗敏感性有关,MAP2可能与OG的预后有关,ATP6V1E1可能与代谢酶的失调有关。
第三部分HMGB1、MAP2、UBA1、ATP6V1E1蛋白在不同1p LOH特征的少枝胶质瘤中的表达及其意义
目的：验证HMGB1、MAP2、UBA1、ATP6V1E1等差异蛋白在不同1p LOH特征的少枝胶质瘤中的表达并分析其意义。
方法：使用Western blot对两组肿瘤中的差异蛋白质UBA1、ATP6V1E1进行验证；并用免疫组化方法对UBA1、ATP6V1E1、MAP2、HMGB1在39例扩大样本中的表达进行验证。
结果：Western blot结果显示UBA1在1p正常组OG中的表达量高于在1pLOH组中的表达量,ATP6V1E1在1p LOH组OG中的表达量高于1p正常组OG中的表达量；免疫组化对扩大样本的HMGB1、MAP2、ATP6V1E1的半定量分析结果显示在1p LOH组OG中的表达较1p正常组高,UBA1的表达在1p正常组OG中较1p LOH组高。
结论：Western blot和免疫组化结果均与蛋白质组学分析结果一致；这些特异蛋白都有望用于免疫组化诊断实现对OG的分子分型,并进一步用于OG的预后判断和指导治疗。
Glioma is the most common primary brain tumor. The incidence of glioma is high and the treatment efficacy has not been satisfactory. Better prognosis of glioma has been achieved with the improvement of surgical technique and the widespread application of chemotherapy and radiotherapy, however the overall prognosis of most gliomas is still poor. Oligodendroglioma(OG) is one major type of gliomas, which accounts for 2-5% of primary brain neoplasms and 4-15% of gliomas. Because these tumors respond well to chemotherapy and have good prognosis, the reason for this is becoming a hot topic in glioma research. It was reported that response to chemotherapy and good prognosis of OG patients were closely related to the presence of allelic losses on lp(or 1p and 19q) in the resected tumor tissue. Further research revealed that OGs with or without 1p LOH had profound differences, such as tumor location, response to radiotherapy, prognosis. So the two types of OGs undistinguishable under optical microscopy may be tumors with different molecular biological character. The molecular classification of OGs may be helpful to their diagnosis and therapy. Except for the difference of lp/19q LOH, other features, such as expression of genes, proteins, and molecular biological mechanisms, are not clearly defined for the OGs. Further studies are needed to elucidate the molecular signatures, and thus possible mechanisms of OGs with 1p LOH.
Modern proteomic technologies allow detection and quantitation of a great number of proteins at the same time. Currently these technologies are being applied in research areas of both basic sciences and clinical medicine. Although genomics and transcriptomics studies have revealed many possible oncogenes and tumor suppressors, proteomics analysis has an advantage of studying proteins, the functional molecule in most of the biological process, directly. In addition to that, post-translational modifications, such as phosphorylation, acetylation, and translocation of the proteins, can only be studied with proteomic technologies. While only a handful of proteins can be studied simultaneously with traditional methods such as western blots, a typical proteomics study would yield information on hundreds or thousands of proteins, which allowed molecular profiling of complex disease such as glioma. Isobaric tags for relative and absolute quantification (iTRAQ) is a new quantitative proteomics technology, which has proved to be efficient, reproducible, and able to simultaneously perform quantitative protein analysis of eight samples. In this study, we use iTRAQ technology combining with two-dimensional liquid chromatography tandem mass spectrometry(2D-LC MS/MS) to identify specific protein markers in OG tissues with 1p LOH.
PartⅠ:Detection of loss of heterozygosity on chromosome 1p in oligodendrogliomas by fluorescence in situ hybridization
Objective:To explore the incidence of loss of heterozygosity (LOH) on chromosome 1p in tissue samples from Chinese patients with oligodendrogliomas.
Methods:Sixteen specimen of oligodendrogliomas and five specimen of normal control cerebral tissues (obtained from the decompression operation of brain trauma) were examined by fluorescence in situ hybridization (FISH).
Results:Of the 16 cases of oligodendrogliomas,10 cases (62.5%) had LOH in chromosome 1p; Of the 6 cases of gradeⅡoligodendrogliomas,5 cases had LOH in 1p; Of the 10 cases ofⅢgrade oligodendrogliomas,5 cases had LOH in 1p.
Conclusion:LOH in chromosome 1p is a frequent characteristic of oligodendrogliomas in Chinese patients. We can distinguish OGs with or without 1p LOH by FISH method effectively and apply FISH in clinical diagnosis.
PartⅡ:iTRAQ-based differential proteomics analysis of oligodendrogliomas
Objective:To perform differential proteomics analysis of oligodendrogliomas with different 1p LOH status; To identify specific proteins for diagnosis and selection of treatment modality.
Methods: Differential proteomics analysis of 8 cases of OGs with different 1p LOH status were performed using iTRAQ combining with 2D-LC MS/MS; the data were analyzed with bioinformatics in the database of DAVID and KEGG; marker proteins were obtained using statistical analysis.
Results:With stringent criteria, we identified 449 proteins from 8 cases of OGs using proteomics analysis; eleven proteins (HMGB1, MAP2, TMSB4X, LRPAP1, MARCKSL1, RPLP2, CISD1, ATP6V1E1, PSAP, PPIF, and ARPC5L) had a higher expression in the OG group with 1p LOH than in the OG group without 1p LOH, while UBA1 and PRKARIA had a higher expression in the OG group without lp LOH than in the OG group with 1p LOH.
Conclusion:There are many differentially expressed proteins between the OGs with and without lp LOH. We obtained a wider coverage of proteins compared to what were found in other studies. Bioinformatics analysis revealed that the actin cytoskeleton pathway may be involved in the molecular biological mechanism of different OGs with and without 1p LOH. HMGB1 and UBA1 may be related to sensitivity of chemotherapy. MAP2 may be related to prognosis.
Part III:The expression of HMGB1, MAP2, UBA1, ATP6V1E1 in OGs with different 1p LOH and its significance
Objective: To examine the expression of HMGB1, MAP2, UBA1, ATP6V1E1 in OGs tissues with different 1p LOH.
Methods:The expression of some of the marker proteins in OGs with different lp LOH were examined using Western blot; the expression of HMGB1, MAP2, UBA1, ATP6V1E1 were further validated in 39 independent OGs tissue samples with different lp LOH status using IHC method.
Results:The result of Western blot confirmed the iTRAQ analysis for the marker proteins; The result of IHC validated that the expression of HMGB1, MAP2 and ATP6V1E1 was higher in OGs with 1p LOH than in OGs without lp LOH, while the expression of UBA1 was higher in OGs without 1p LOH than in OGs with 1p LOH.
Conclusion:The results of Western blot and IHC were consistent with the iTRAQ-based proteomics analysis; These specific proteins may be useful in diagnosis, prognosis and treatment selection for OG patients.
蛋白质组学分析是一个能同时研究大量蛋白质及其表达变化的方法,正逐渐应用于从基础科学到临床实践科学的广泛领域中,受到前所未有的重视。在人类基因组计划的推动下,人们从基因水平对肿瘤进行了广泛的研究,并且发现了许多与肿瘤相关的基因,包括一些与肿瘤治病有关的致癌基因和抑癌基因,但基因的功能活动最终要靠蛋白质来体现。众所周知,从DNA-mRNA-蛋白质的过程中存在着转录后剪切和翻译后的修饰加工,以及蛋白质合成后的转移定位等多种变化,所以DNA和mRNA的水平和状况并不完全代表蛋白质的水平和状况。而以往的蛋白质研究方法如Western blot等一次只能对一个或几个蛋白质的表达进行研究。但我们现在知道肿瘤的分子生物学机制都是涉及成百上千个蛋白活动的过程,因此,有必要从蛋白质整体水平来研究、寻找出与肿瘤相关的特征蛋白质,阐明其机制。同位素标记相对和绝对定量(iTRAQ)技术是近年来新开发的一种蛋白质组学定量研究技术,具有较好的定量效果、较高的重复性,并可对多达8种不同样本同时进行定量分析。因此,iTRAQ标记-串联质谱分析技术是寻找疾病和肿瘤发生过程中的标志性蛋白或者称为Biomarker的理想方法。我们此次使用iTRAQ技术结合多维液相色谱串联质谱(2D-LC MS/MS)对不同1pLOH特征的少枝胶质瘤组织进行比较蛋白质组分析,寻找特异蛋白作为诊断标志并进一步探求不同少枝胶质瘤的发病机制。
第一部分荧光原位杂交技术检测少枝胶质瘤1p染色体的杂合性缺失
目的：研究少枝胶质瘤中1p染色体的杂合性缺失。
方法：使用荧光原位杂交技术对16例少枝胶质瘤标本及5例正常对照脑组织行1p染色体检测。
结果：在16例少枝胶质瘤中有10例有1p染色体的杂合性缺失,占62.5%,其中6例Ⅱ级肿瘤中有5例缺失,10例Ⅲ级肿瘤中有5例缺失。
结论：1p染色体杂合性缺失是少枝胶质瘤的重要分子生物学特征,通过荧光原位杂交技术,我们可以对这两类少枝胶质瘤有效地加以区分,并用于进一步的临床诊断和治疗。
第二部分基于iTRAQ技术的少枝胶质瘤差异蛋白质组分析
目的：对不同1p LOH特征的少枝胶质瘤进行差异蛋白质组分析,寻找特异蛋白用于诊断和治疗。
方法：使用同位素标记相对和绝对定量(iTRAQ)技术结合多维液相色谱串联质谱(2D-LC MS/MS)的定量蛋白质组学方法对8例不同1p LOH特征的两组少枝胶质瘤进行分析,并用DAVID、KEGG软件对数据进一步处理行生物信息学分析,通过统计分析找出差异蛋白质。
结果：通过蛋白质组分析在8例少枝胶质瘤中共鉴定得到449个蛋白质,统计分析发现HMGB1、MAP2、TMSB4X、LRPAP1、MARCKSL1、RPLP2、CISD1、ATP6V1E1、PSAP、PPIF、ARPC5L这11个蛋白在1p LOH的OG中表达较1p正常组肿瘤高,UBA1、PRKAR1A两个蛋白在1p正常的OG中表达较1p LOH组肿瘤高。
结论：在两组不同1p LOH特征的少枝胶质瘤中找到多个有差异表达的蛋白质,较其它蛋白质组学方法找到的蛋白谱范围更广；生物信息学分析显示Actin cytoskeleton通路的不同可能与这两类肿瘤的不同机制有关,HMGB1、UBA1可能与OG的化疗敏感性有关,MAP2可能与OG的预后有关,ATP6V1E1可能与代谢酶的失调有关。
第三部分HMGB1、MAP2、UBA1、ATP6V1E1蛋白在不同1p LOH特征的少枝胶质瘤中的表达及其意义
目的：验证HMGB1、MAP2、UBA1、ATP6V1E1等差异蛋白在不同1p LOH特征的少枝胶质瘤中的表达并分析其意义。
方法：使用Western blot对两组肿瘤中的差异蛋白质UBA1、ATP6V1E1进行验证；并用免疫组化方法对UBA1、ATP6V1E1、MAP2、HMGB1在39例扩大样本中的表达进行验证。
结果：Western blot结果显示UBA1在1p正常组OG中的表达量高于在1pLOH组中的表达量,ATP6V1E1在1p LOH组OG中的表达量高于1p正常组OG中的表达量；免疫组化对扩大样本的HMGB1、MAP2、ATP6V1E1的半定量分析结果显示在1p LOH组OG中的表达较1p正常组高,UBA1的表达在1p正常组OG中较1p LOH组高。
结论：Western blot和免疫组化结果均与蛋白质组学分析结果一致；这些特异蛋白都有望用于免疫组化诊断实现对OG的分子分型,并进一步用于OG的预后判断和指导治疗。
Glioma is the most common primary brain tumor. The incidence of glioma is high and the treatment efficacy has not been satisfactory. Better prognosis of glioma has been achieved with the improvement of surgical technique and the widespread application of chemotherapy and radiotherapy, however the overall prognosis of most gliomas is still poor. Oligodendroglioma(OG) is one major type of gliomas, which accounts for 2-5% of primary brain neoplasms and 4-15% of gliomas. Because these tumors respond well to chemotherapy and have good prognosis, the reason for this is becoming a hot topic in glioma research. It was reported that response to chemotherapy and good prognosis of OG patients were closely related to the presence of allelic losses on lp(or 1p and 19q) in the resected tumor tissue. Further research revealed that OGs with or without 1p LOH had profound differences, such as tumor location, response to radiotherapy, prognosis. So the two types of OGs undistinguishable under optical microscopy may be tumors with different molecular biological character. The molecular classification of OGs may be helpful to their diagnosis and therapy. Except for the difference of lp/19q LOH, other features, such as expression of genes, proteins, and molecular biological mechanisms, are not clearly defined for the OGs. Further studies are needed to elucidate the molecular signatures, and thus possible mechanisms of OGs with 1p LOH.
Modern proteomic technologies allow detection and quantitation of a great number of proteins at the same time. Currently these technologies are being applied in research areas of both basic sciences and clinical medicine. Although genomics and transcriptomics studies have revealed many possible oncogenes and tumor suppressors, proteomics analysis has an advantage of studying proteins, the functional molecule in most of the biological process, directly. In addition to that, post-translational modifications, such as phosphorylation, acetylation, and translocation of the proteins, can only be studied with proteomic technologies. While only a handful of proteins can be studied simultaneously with traditional methods such as western blots, a typical proteomics study would yield information on hundreds or thousands of proteins, which allowed molecular profiling of complex disease such as glioma. Isobaric tags for relative and absolute quantification (iTRAQ) is a new quantitative proteomics technology, which has proved to be efficient, reproducible, and able to simultaneously perform quantitative protein analysis of eight samples. In this study, we use iTRAQ technology combining with two-dimensional liquid chromatography tandem mass spectrometry(2D-LC MS/MS) to identify specific protein markers in OG tissues with 1p LOH.
PartⅠ:Detection of loss of heterozygosity on chromosome 1p in oligodendrogliomas by fluorescence in situ hybridization
Objective:To explore the incidence of loss of heterozygosity (LOH) on chromosome 1p in tissue samples from Chinese patients with oligodendrogliomas.
Methods:Sixteen specimen of oligodendrogliomas and five specimen of normal control cerebral tissues (obtained from the decompression operation of brain trauma) were examined by fluorescence in situ hybridization (FISH).
Results:Of the 16 cases of oligodendrogliomas,10 cases (62.5%) had LOH in chromosome 1p; Of the 6 cases of gradeⅡoligodendrogliomas,5 cases had LOH in 1p; Of the 10 cases ofⅢgrade oligodendrogliomas,5 cases had LOH in 1p.
Conclusion:LOH in chromosome 1p is a frequent characteristic of oligodendrogliomas in Chinese patients. We can distinguish OGs with or without 1p LOH by FISH method effectively and apply FISH in clinical diagnosis.
PartⅡ:iTRAQ-based differential proteomics analysis of oligodendrogliomas
Objective:To perform differential proteomics analysis of oligodendrogliomas with different 1p LOH status; To identify specific proteins for diagnosis and selection of treatment modality.
Methods: Differential proteomics analysis of 8 cases of OGs with different 1p LOH status were performed using iTRAQ combining with 2D-LC MS/MS; the data were analyzed with bioinformatics in the database of DAVID and KEGG; marker proteins were obtained using statistical analysis.
Results:With stringent criteria, we identified 449 proteins from 8 cases of OGs using proteomics analysis; eleven proteins (HMGB1, MAP2, TMSB4X, LRPAP1, MARCKSL1, RPLP2, CISD1, ATP6V1E1, PSAP, PPIF, and ARPC5L) had a higher expression in the OG group with 1p LOH than in the OG group without 1p LOH, while UBA1 and PRKARIA had a higher expression in the OG group without lp LOH than in the OG group with 1p LOH.
Conclusion:There are many differentially expressed proteins between the OGs with and without lp LOH. We obtained a wider coverage of proteins compared to what were found in other studies. Bioinformatics analysis revealed that the actin cytoskeleton pathway may be involved in the molecular biological mechanism of different OGs with and without 1p LOH. HMGB1 and UBA1 may be related to sensitivity of chemotherapy. MAP2 may be related to prognosis.
Part III:The expression of HMGB1, MAP2, UBA1, ATP6V1E1 in OGs with different 1p LOH and its significance
Objective: To examine the expression of HMGB1, MAP2, UBA1, ATP6V1E1 in OGs tissues with different 1p LOH.
Methods:The expression of some of the marker proteins in OGs with different lp LOH were examined using Western blot; the expression of HMGB1, MAP2, UBA1, ATP6V1E1 were further validated in 39 independent OGs tissue samples with different lp LOH status using IHC method.
Results:The result of Western blot confirmed the iTRAQ analysis for the marker proteins; The result of IHC validated that the expression of HMGB1, MAP2 and ATP6V1E1 was higher in OGs with 1p LOH than in OGs without lp LOH, while the expression of UBA1 was higher in OGs without 1p LOH than in OGs with 1p LOH.
Conclusion:The results of Western blot and IHC were consistent with the iTRAQ-based proteomics analysis; These specific proteins may be useful in diagnosis, prognosis and treatment selection for OG patients.
引文
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6. Tanaka Y, Yokoo H, Komori T, et al. A distinct pattern of olig2-positive celluar distribution in papillary glioneuronal tumors:a manifestation of the oligodendroglial phenotype? [J]. Acta Neuropathol,2005,110:39-47.
7. Smith JS, Perry A, Borell TJ, et al. Alterations of chromosome armslp and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas [J]. J Clin Oncol,2000,18:636-645.
8. Mukasa A, Ueki K, Matsumoto S, et al. Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p [J]. Oncogene, 2002,21:3961-3968.
9. Mischel PS, Shai R, Shi T, et al. Identification of molecular subtypes of glioblastoma by gene expression profiling [J]. Oncogene,2003,22:2361-2373.
10. Shai R, Shi T, Kremen TJ, et al. Gene expression profiling identifies molecular subtypes of gliomas [J]. Oncogene,2003,22:4918-4923.
11. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression [J]. Nature, 2002,415:436-442.
12. Roversi G, Pfundt R, Moroni RF, et al. Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines [J]. Oncogene,2006,25:1571-1583.
13.Hanash SM, Bobek MP, Richman DS, et al. Integrating cancer genomics and proteomics in the post-genome era [J]. Proteomics,2002,2:69-75.
14. Trog D, Fountoulakis M, Friedlein A, et al. Is current therapy of malignant gliomas beneficial for patients? Proteomics evidence of shifts in glioma cells expression patterns under clinically relevant theatment conditions [J]. Proteomics, 2006,6:2924-2930.
15. Furuta M. Weil RJ, Vortmeyer AO, et al. Protein patterns and protein that identify subtypes of glioblastoma multiforme. Oncogene,2004,23:6806-6814.
16. Khalil AA.Biomarker discovery: A proteomic approach for brain cancer profiling [J]. Cancer Sci,2007,98:201-213.
17. Iwadate Y, Sakaida T, Hiwasa T, et al. Molecular classification and survival prediction in human gliomas based on proteome analysis [J]. Cancer Res, 2004.64:2496-2501.
18. Chumbbalkar VC, Subhashini C, Dhople VM, et al. Differential protein expression in human gliomas and molecular insights [J]. Proteomics, 2005,5:1167-1177.
19. Li J, Zhuang Z, Okamoto H, et al. Proteomic profiling distinguishes astrocytomas and identifies differential tumor markers [J]. Neurology,2006,66:733-736.
20. Scheartz SA, Weil RJ, Thompson RC, et al. Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-assisted laser desorption ionization mass spectrometry. Cancer Res,2005,65:7674-7681.
21. Okamoto H, Li J, Glasker S, Vortmeyer AO, et al. Proteomic comparison of oligodendrogliomas with and without 1p LOH [J]. Cancer Biol Ther, 2007,6(3):391-6.
22.何大澄,肖雪媛.差异蛋白质组学及其应用[J].北京师范大学学报(自然科学版),2002,38(4)：558-562.
23.李选文,陈平,张丽军等.癌症差异蛋白质组学研究中样品分离和鉴定分析技术[J].生命科学,2007,19(1)：97-103.
1. Kleihues P, Cavenee WK. Pathology and genetics of tumors of the nervous system[M]. World Health Organization Classification of Tumors. Lyon: IARC Press,2000:72-77.
2. Engelhard HH, Stelea, A, Mundt A. Oligodendroglioma and anaplastic oligodendroglioma: clinical features, treatment, and prognosis [J]. Surg Neurol, 2003,60(5):443-456.
3. Reifenberger G, Louis D. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology [J]. J Neuropathol Exp Neurol,2003,62(2):111-126.
4. Engelhard HH, Stelea A, Cochran EJ, et al. Oligodendroglioma: pathology and molecular biology [J]. Surg Neurol,2002,58(2):111-117.
5. Jenkins RB, Qian J, Lee HK, et al. A molecular cytogenetic analysis of 7q31 in prostate cancer [J]. Cancer Res,1998,58:759-766.
6. Gelpi E, Ambros IM, Birner P, et al. Fluorescent in situ hybridization on isolated tumor cell nuclei:a sensitive method for 1p and 19q deletion analysis in paraffin-embedded oligodendroglial tumor specimens [J]. Mod Pathol, 2003,16(7):708-715.
7. Jenkins RB, Qian J, Lieber MM, et al. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization [J]. Cancer Res,1997,57:524-531.
8. Scheie D, Andresen PA, Cvancarova M, et al. Fluorescence in situ hybridization (FISH) on touch preparations:a reliable method for detecting loss of heterozygosity at 1p and 19q in oligodendroglial tumors [J]. Am J Surg Path, 2006,30(7):828-837.
9. Dalrymple SJ, Herath TF, Ritland SR, et al. Use of fluorescence in situ hybridization to detect loss of chromosome 10 in astrocytomas [J]. J Neurosurg 1995,83:316-323.
10. Tanaka Y, Yokoo H, Komori T, et al. A distinct pattern of Olig2-positive celluar distribution in papillary glioneuronal tumors:a manifestation of the oligodendroglial phenotype [J]. Acta Neuropathol,2005,110(1):39-47
11. Kros JM, Gorlia T, Kouwenhoven MC, et al. Panel review of anaplastic oligodendroglioma from European organization for research and treatment of cancer trial 26951:assessment of consensus in diagnosis, influence of lp/19q loss, and correlations with outcome [J]. J Neuropathol Exp Neurol, 2007,66(6):545-551.
12. Burger PC, Rawlings CE, Cox EB, et al. Clinicopathologic correlations in the oligodendroglima [J]. Cancer,1987,59(7):1345-1352.
13. Hamlat A, Saikali S, Chaperon J, et al. Proposal of a scoring scale as a survival predictor in intracranial oligodendrogliomas [J]. J Neurooncol, 2006,79(2):159-168.
14. Ozyigit G, Onal C, Gurkaynak M, et al. Postoperative radiotherapy and chemotherapy in the management of oligodendroglioma: singlie institutional review of 88 patients [J]. J Neurooncol,2005,75(2):189-193.
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17. Smith JS, Alderete B, Minn Y, et al. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype [J]. Oncogene,1999,18(28):4144-4152.
18. Jenkins RB, Qian J, Lieber MM, et al. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization [J]. Cancer Res,1997,57(3):524-531.
19. Jenkins RB, Qian J, Lee HK, et al. A molecular cytogenetic analysis of 7q31 in prostate cancer [J]. Cancer Res,1998,58(4):759-766.
20. Fuller CE, Schmidt RE, Roth KA, et al. Clinical utility of fluorescence in situ hybridization in morphologically ambiguous gliomas with hybrid oligodendroglial/astrocytic features [J]. J Neuropathol Exp Neurol, 2003,62(11).1118-1128.
21. Smith JS, Perry A, Borell TJ, et al. Alteration of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas [J]. J Clin Oncol,2000,18(3):636-645.
22.桂秋萍,乔广宇,许冠东等.胶质细胞瘤染色体1p杂合性缺失：14例研究分析[J].中国神经肿瘤杂志,2007,5(2)：103-107.
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3. Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology [J]. J Neuropathol Exp Neurol,2003,62(2):111-126.
4. Kros JM, Gorlia T, Kouwenhoven MC, Zheng PP, et al. Panel review of anaplatic oligodendroglioma from European Organization for research and treatment of cancer trial 26951:assessment of consensus in diagnosis, influence of lp/19q loss, and correlations with outcome [J]. J Neuropathol Exp Neurol,2007,66(6)545-551.
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6. Mukasa A, Ueki K, Matsumoto S, et al. Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p [J]. Oncogene, 2001,21:3961-3968.
7. Hanash SM, Bobek MP, Richman DS, et al. Integrating cancer genomics and proteomics in the post-genome era [J]. Proteomics,2002,2:69-75.
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1 Boudreau C, Yang I, Liau ML. Gliomas: advances in molecular analysis and characterization [J]. Surg Neurol,2005,64:286-294.
2 Sanson M, Thillet J, Xuan KH. Molecular changes in glioma [J]. Curr Opin Oncol, 2004,16:607-613.
3 Tanaka Y, Yokoo H, Komori T, et al. A distinct pattern of olig2-positive celluar distribution in papillary glioneuronal tumors: a manifestation of the oligodendroglial phenotype [J]. Acta Neuropathol,2005,110:39-47.
4 Ichimura K, Ohgaki H, Kleihues P, et al. Molecular pathogenesis of astrocytic tumors [J]. J Neuro-oncol,2004,70:137-160.
5 Chakravarti A, Dicker A, Mehta M. The contribution of epidermal growth factor receptor(EGFR) signaling pathway to radioresistance in human gliomas:A review of preclinical and correlative clinical data [J]. Int J Radiation Oncology Biol Phys,2004,58(3):927-931.
6 Li J, Zhang Z, Okamoto H, et al. Proteomic profiling distinguishes astrocytomas and identifies differential tumor markers [J]. Neurology,2006,66:733-736.
7 Mischel PS, Cloughesy TF, Nelson SF. DNA-microarray analysis of brain cancer: molecular classification for therapy [J]. Nature reviews/neuroscience,2004,5:782-792.
8 Shai R, Shi T, Kremen TJ, et al. Gene expression profiling identifies molecular subtypes of gliomas [J]. Oncogene,2003,22:4918-4923.
9 Mischel PS, Shai R, Shi T, et al. Identification of molecular subtypes of glioblastoma by gene expression profiling [J]. Oncogene,2003,22:2361-2373.
10 Kim S, Dougherty ER, Shmulevich I, et al. Identification of combination gene sets for glioma classification [J]. Mol Cancer Ther,2002,1:1229-1236.
11 Nutt CL, Mani DR, Betensky RA, et al. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification [J]. Cancer Res, 2003.63:1602-1607.
12 Phillips HS, Kharbanda S, Chen R, et al. Molecular subclass of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis [J]. Cancer Cell,2006,9:157-173.
13 Hanash SW, Bobek MP, Richman DS, et al. Integrating cancer genomics and proteomics in the post-genome era [J]. Proteomics,2002,2:69-75.
14 Khalil AA. Biomarker discovery: A proteomic approach for brain cancer profiling [J]. Cancer Sci,2007,98(2):201-213.
15 Furuta M, Weil RJ, Vortmeyer AO, et al. Protein patterns and proteins that identify subtypes of glioblastoma multiforme [J]. Oncogene,2004,23:6806-6814.
16 Iwadate Y, Sakaida T, Hiwasa T, et al. Molecular classification and survival prediction in human gliomas based on proteome analysis [J]. Cancer Res,2004,64:2496-2501.
17 Schwartz SA, Weil RJ, Thompson RC, et al. Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-assisted laser desorption ionization mass spectrometry [J]. Cancer Res, 2005,65(17):7674-7681.
2. Boudreau C, Yang I, Liau ML. Gliomas:advances in molecular analysis and characterization [J]. Surg Neurol,2005,64:286-294.
3. Sanson M, Thillet J, Xuan KH. Molecular changes in glioma [J]. Curr Opin Oncol, 2004,16:607-613.
4. Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuron-oncology [J]. J Neuropathol Exp Neur,2003,62(2):111-126.
5. Engelhard HH, Stelea A, Cochran EJ, et al. Oligodendroglioma: pathology and molecular biology [J]. Surg Neurol,2002,58:111-117.
6. Tanaka Y, Yokoo H, Komori T, et al. A distinct pattern of olig2-positive celluar distribution in papillary glioneuronal tumors:a manifestation of the oligodendroglial phenotype? [J]. Acta Neuropathol,2005,110:39-47.
7. Smith JS, Perry A, Borell TJ, et al. Alterations of chromosome armslp and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas [J]. J Clin Oncol,2000,18:636-645.
8. Mukasa A, Ueki K, Matsumoto S, et al. Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p [J]. Oncogene, 2002,21:3961-3968.
9. Mischel PS, Shai R, Shi T, et al. Identification of molecular subtypes of glioblastoma by gene expression profiling [J]. Oncogene,2003,22:2361-2373.
10. Shai R, Shi T, Kremen TJ, et al. Gene expression profiling identifies molecular subtypes of gliomas [J]. Oncogene,2003,22:4918-4923.
11. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression [J]. Nature, 2002,415:436-442.
12. Roversi G, Pfundt R, Moroni RF, et al. Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines [J]. Oncogene,2006,25:1571-1583.
13.Hanash SM, Bobek MP, Richman DS, et al. Integrating cancer genomics and proteomics in the post-genome era [J]. Proteomics,2002,2:69-75.
14. Trog D, Fountoulakis M, Friedlein A, et al. Is current therapy of malignant gliomas beneficial for patients? Proteomics evidence of shifts in glioma cells expression patterns under clinically relevant theatment conditions [J]. Proteomics, 2006,6:2924-2930.
15. Furuta M. Weil RJ, Vortmeyer AO, et al. Protein patterns and protein that identify subtypes of glioblastoma multiforme. Oncogene,2004,23:6806-6814.
16. Khalil AA.Biomarker discovery: A proteomic approach for brain cancer profiling [J]. Cancer Sci,2007,98:201-213.
17. Iwadate Y, Sakaida T, Hiwasa T, et al. Molecular classification and survival prediction in human gliomas based on proteome analysis [J]. Cancer Res, 2004.64:2496-2501.
18. Chumbbalkar VC, Subhashini C, Dhople VM, et al. Differential protein expression in human gliomas and molecular insights [J]. Proteomics, 2005,5:1167-1177.
19. Li J, Zhuang Z, Okamoto H, et al. Proteomic profiling distinguishes astrocytomas and identifies differential tumor markers [J]. Neurology,2006,66:733-736.
20. Scheartz SA, Weil RJ, Thompson RC, et al. Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-assisted laser desorption ionization mass spectrometry. Cancer Res,2005,65:7674-7681.
21. Okamoto H, Li J, Glasker S, Vortmeyer AO, et al. Proteomic comparison of oligodendrogliomas with and without 1p LOH [J]. Cancer Biol Ther, 2007,6(3):391-6.
22.何大澄,肖雪媛.差异蛋白质组学及其应用[J].北京师范大学学报(自然科学版),2002,38(4)：558-562.
23.李选文,陈平,张丽军等.癌症差异蛋白质组学研究中样品分离和鉴定分析技术[J].生命科学,2007,19(1)：97-103.
1. Kleihues P, Cavenee WK. Pathology and genetics of tumors of the nervous system[M]. World Health Organization Classification of Tumors. Lyon: IARC Press,2000:72-77.
2. Engelhard HH, Stelea, A, Mundt A. Oligodendroglioma and anaplastic oligodendroglioma: clinical features, treatment, and prognosis [J]. Surg Neurol, 2003,60(5):443-456.
3. Reifenberger G, Louis D. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology [J]. J Neuropathol Exp Neurol,2003,62(2):111-126.
4. Engelhard HH, Stelea A, Cochran EJ, et al. Oligodendroglioma: pathology and molecular biology [J]. Surg Neurol,2002,58(2):111-117.
5. Jenkins RB, Qian J, Lee HK, et al. A molecular cytogenetic analysis of 7q31 in prostate cancer [J]. Cancer Res,1998,58:759-766.
6. Gelpi E, Ambros IM, Birner P, et al. Fluorescent in situ hybridization on isolated tumor cell nuclei:a sensitive method for 1p and 19q deletion analysis in paraffin-embedded oligodendroglial tumor specimens [J]. Mod Pathol, 2003,16(7):708-715.
7. Jenkins RB, Qian J, Lieber MM, et al. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization [J]. Cancer Res,1997,57:524-531.
8. Scheie D, Andresen PA, Cvancarova M, et al. Fluorescence in situ hybridization (FISH) on touch preparations:a reliable method for detecting loss of heterozygosity at 1p and 19q in oligodendroglial tumors [J]. Am J Surg Path, 2006,30(7):828-837.
9. Dalrymple SJ, Herath TF, Ritland SR, et al. Use of fluorescence in situ hybridization to detect loss of chromosome 10 in astrocytomas [J]. J Neurosurg 1995,83:316-323.
10. Tanaka Y, Yokoo H, Komori T, et al. A distinct pattern of Olig2-positive celluar distribution in papillary glioneuronal tumors:a manifestation of the oligodendroglial phenotype [J]. Acta Neuropathol,2005,110(1):39-47
11. Kros JM, Gorlia T, Kouwenhoven MC, et al. Panel review of anaplastic oligodendroglioma from European organization for research and treatment of cancer trial 26951:assessment of consensus in diagnosis, influence of lp/19q loss, and correlations with outcome [J]. J Neuropathol Exp Neurol, 2007,66(6):545-551.
12. Burger PC, Rawlings CE, Cox EB, et al. Clinicopathologic correlations in the oligodendroglima [J]. Cancer,1987,59(7):1345-1352.
13. Hamlat A, Saikali S, Chaperon J, et al. Proposal of a scoring scale as a survival predictor in intracranial oligodendrogliomas [J]. J Neurooncol, 2006,79(2):159-168.
14. Ozyigit G, Onal C, Gurkaynak M, et al. Postoperative radiotherapy and chemotherapy in the management of oligodendroglioma: singlie institutional review of 88 patients [J]. J Neurooncol,2005,75(2):189-193.
15. Ueki K, Nishikawa R, Nakazato Y, et al. Correlation of histology and molecular genetic analysis of 1p,19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors [J]. Clin Cancer Res,2002,8(1):196-201.
16. Burger PC, Minn AY, Smith JS, et al. Losses of chromosomal arms 1p and 19q in the diagnosis of oligodendroglioma: A study of paraffin-embedded sections [J]. Mod Pathol,2001,14(9):842-853.
17. Smith JS, Alderete B, Minn Y, et al. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype [J]. Oncogene,1999,18(28):4144-4152.
18. Jenkins RB, Qian J, Lieber MM, et al. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization [J]. Cancer Res,1997,57(3):524-531.
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